While many studies show that a variety of immunotherapies can effectuate substantial tumor destruction, much less is known regarding the generation of endogenous anti-tumor responses and their importance to spontaneous tumor formation. Multiple defects in anti-tumor immunity have been described in tumor-bearing hosts, including tumor-specific T cell anergy, tolerance, deletion, and indifference; progressive tumor growth in these cases indicates the absence or failure of tumor defense. In contrast, other work demonstrates that perforin, interferon-gamma (IFN-gamma), interleukin-12 (IL-12), invariant NKT cell, and RAG2 deficient mice develop more tumors in response to chemical carcinogens than wild type littermates. Moreover, aged perforin or fas-fas ligand deficient mice spontaneously form lymphomas, and aged RAG2 and STAT1 doubly deficient mice spontaneously develop carcinomas of the intestine, lung, and breast. Together, these studies illustrate that some endogenous immune responses can modulate tumor formation. Here we show that mice doubly deficient in granulocyte-macrophage colony stimulating factor (GM-CSF) and IFN-gamma or triply deficient in GM-CSF, IFN-gamma, and interleukin-3 (IL-3), to a greater degree, spontaneously develop diverse hematologic and solid tumors in association with infection and inflammatory disease. The unexpected high frequency and broad spectrum of tumors implies that cytokine-mediated regulation of cell growth and immune homeostasis is a critical determinant of cancer susceptibility. However, the mechanisms by which multiple cytokine deficiencies lead to spontaneous tumor development remain to be clarified. In this application, we propose a series of investigations to establish the contributions of compromised immunity, chronic infection, and chronic inflammation to spontaneous tumor formation. These studies should deepen our understanding of protective host responses against tumor development and provide a more detailed framework for designing immunotherapies against incipient and established tumors. The specific aims of this project are: 1) To characterize anti-tumor immunity in GM-CSF, IL-3, and IFN-gamma deficient mice. 2) To determine the impact of chronic infection and inflammation on tumor development in GM-CSF, IL-3, and IFN-gamma deficient mice. 3). To develop strategies for reconstituting tumor defense in mice deficient in GM-CSF, IL-3, and IFN-gamma.